1. Field of the Invention
This invention relates to phenylcycloalkylmethylamino and phenylalkenylamino derivatives, including 1-phenyl-2-aminomethylcyclopropanes, that are modulators of melanin concentrating hormone type 1 (MCH 1) receptors. This invention also relates to pharmaceutical compositions comprising such compounds.
2. Description of the Related Art
Melanin concentrating hormone, or MCH, is a cyclic 19 amino acid neuropeptide that is produced within the hypothalamus of many vertebrate species including man. I.C.V. injection of MCH into the lateral ventricle of the hypothalamus has been shown to increase caloric consumption in rats over similarly treated control animals. Furthermore, rats having the ob/ob genotype exhibit a 50-80% increase in MCH mRNA expression as compared to leaner ob/+ genotype mice. MCH knockout mice are leaner than their MCH-producing siblings due to hypophagia and an increased metabolic rate. Thus, MCH is thought to be an important regulator of feeding behavior and body weight.
The MCH 1 receptor was originally obtained from human cDNA and genomic libraries and characterized as a 402 amino acid G-coupled protein receptor having substantial sequence identity to the somatostatin receptors. This receptor was named the SLC-1 receptor. A rat orthologue of the MCH 1 receptor was isolated from a rat brain cDNA library by Lakaye, et al. (BBA (1998) 1401: 216-220) and found to encode a 353 amino acid protein having seven transmembrane alpha helices and three consensus N-glycosylation sites. The rat MCH 1 receptor reported by Lakaye also disclosed was homologous to the human MCH 1 receptor disclosed earlier except for the removal of a 5′ intron. Accordingly, Lakaye, et al., deduced the “corrected” amino acid sequence of the N-terminus of MCH 1 receptor is found within a sequence deposited for a 128 kb fragment of human chromosome 22 encompassing the earlier disclosed MCH 1 receptor gene (Genbank accession number: Z86090).
The earlier reported 402 amino acid MCH 1 receptor protein does not interact with MCH. Thus, the 353 amino acid receptor first reported by Lakaye, is now considered to be the correct full-length sequence for the human MCH 1 receptor.
Immunohistochemistry studies of rat brain sections indicate that the MCH 1 receptor is widely expressed in the brain. MCH 1 receptor expression was found in the olfactory tubercle, cerebral cortex, substantia nigra, basal forebrain CA1, CA2, and CA3 field of the hippocampus, amygdala, and in nuclei in the hypothalamus, thalamus, midbrain and hindbrain. Strong signals have been observed in the ventromedial and dorsomedial nuclei of the hypothalamus, two areas of the brain known to be involved in feeding behavior.
Upon binding MCH, MCH 1 receptors expressed in HEK 293 cell mediate a dose dependent release of intracellular calcium. Cells expressing MCH receptors have also been shown to exhibit a pertussis toxin sensitive dose-dependent inhibition of forskolin-elevated cyclic AMP, indicating that the receptor couples to a Gi/o G-protein alpha subunit.
Because MCH has been shown to be an important regulator of food intake and energy balance, ligands capable of modulating the activity of the MCH 1 receptor are highly desirable for the treatment of eating disorders and metabolic disorders. Orally available, small molecule, non-peptide antagonists of the MCH 1 receptor are particularly sought for the treatment of obesity.